Transcriptome and DNA Methylome Signatures Associated With Retinal Müller Glia Development, Injury Response, and Aging

Purpose The purpose of this study was to systematically characterize and correlate the transcriptome and DNA methylome signatures of mouse Muller cells that may underlie the development, physiological functions, and regeneration capacity of these cells. Methods Mouse Muller cells under normal, injury, and aging conditions were sorted from Muller cell-specific green fluorescent protein (GFP)-expressing mice. RNA sequencing was used to sequence transcriptomes, and reduced representation bisulfite sequencing was used to sequence DNA methylomes. Various bioinformatics tools were used to compare and correlate the transcriptomes and DNA methylomes. Results Muller cells express a distinct transcriptome that is in line with their retinal supporting roles and dormant retinogenic status. Injury changes the Muller cell transcriptome dramatically but fails to stimulate the cell cycle machinery and retinogenic factors to the states observed in early retinal progenitor cells (RPCs). Muller cells exhibit a less methylated genome than that of early RPCs, but most regulatory elements for Muller cell- and RPC-specific genes are similarly hypomethylated in both Muller cells and RPCs, except for a subset of Muller cell-specific functional genes. Aging only subtly affects the transcriptome and DNA methylome of Muller cells. Conclusions Failure to reactivate the cell cycle machinery and retinogenic factors to necessary levels might be key barriers blocking Muller cells from entering an RPC-like regeneration state. DNA methylation might regulate the expression of a subset of Muller cell-specific functional genes during development but is likely not involved in restricting the regeneration activity of Muller cells.